The film's setting is an archaeological dig at "Olduvai" on Mars. Earth's Olduvai Gorge contains some of the earliest human and hominid (pre-human) remains and artifacts. This was the setting for the opening scenes of 2001: A Space Odyssey (1968).

The names of scientists Dr. Todd Carmack and Dr. Willits are references to Todd Hollenshead, John Carmack and Tim Willits, co-owners of id Software, and developers of the Doom game and its sequels, including Doom³ (2004) upon which this movie is based.

Originally, it was announced in 1999 that the film would be made and that Arnold Schwarzenegger was cast in the lead role of Doomguy, the protagonist of the video game. Unfortunately, a real life incident involving two teenagers who had played the video game, playing about with a chainsaw, resulted in a tragic accident. Since one of Doomguy's weapons in the video game is a chainsaw, the film with Schwarzenegger in the lead role was dropped at that time. The film was finally brought to the big screen in 2005.

In one of the many references to the game the film is based on - the most notable, of course, being the FPS sequence - the flange on the weapon lights has a six-lobed design which gives the light a hexagonal shape when viewed from (or nearly from) the front. This imitates the hexagonal shape often seen on supposedly round things, and very noticeably such things as flashlights, in video games (because the shape is easier to handle by computer hardware than a truly round shape).

During the end credits, a remixed version of the song "You Know What You Are" by Nine Inch Nails plays. Trent Reznor, NIN frontman, headed up the music and sound design for Quake (1996), which was also created by id Software.

When Sarge uses the severed hand to open the advanced weapons armory, the computer voice (and subtitles) say, "Welcome, Dr. Patricia Tallman." The character is named in the credits as Dr. Hillary Tallman. Much like the inclusion of John Carmack's name, this is a subtle insider reference, but one that is arguably more likely to be noticed than the name of ID Software's infamous co-founder Carmack.

The character Goat's seemingly malevolent personality is a hint to the animal of the same name's involvement and connection with modern Satanism, which is a reference to the original Doom video game series, which implied the monsters in the game as being demons spawned from hell.